Radiation therapy is utilized to treat approximately 50% of all patients with cancer. However, a fundamental gap in improving the efficacy of radiation therapy is that the mechanisms by which radiotherapy controls tumors remain poorly understood. For example, it is controversial whether tumor endothelial cells are a critical target of radiation therapy, which mediate tumor cure. The overall goal of this research is to define the cellular target of radiation therapy: tumor cells (referred to here as tumor parenchymal cells) vs. endothelial cells. The central hypothesis of this application is that radiation therapy cures cance by killing tumor parenchymal cells rather than tumor endothelial cells. To study the relative contribution of tumor endothelial cells and tumor parenchymal cells as targets of radiation therapy, we have generated novel genetically engineered mice. Previously, we used Cre recombinase to develop genetically engineered mouse models of lung cancer and soft tissue sarcoma to study radiation biology. We have now generated novel strains of genetically engineered mice in which primary cancers can be generated with Flp recombinase. In this system, Cre recombinase can still be utilized to modify genes specifically in tumor endothelial cells. Utilizing Flp and Cre recombinases (ie dual recombinase technology) to study the role of tumor endothelial cells in radiation therapy is highly innovative because primary cancers can be initiated with one recombinase, while the other recombinase can be utilized to specifically modify the radiosensitivity of the endothelial cells. The proposed research is significant, because it will clarify whether tumor endothelial cells are a critical target for radiation therapy Ultimately, such knowledge has the potential to lay the foundation for novel approaches to improve the efficacy of radiation therapy.